NLRC5 promotes transcription of BTN3A1-3 genes and Vγ9Vδ2 T cell-mediated killing
Anh Thu Dang,
Juliane Strietz,
Alessandro Zenobi,
Hanif J. Khameneh,
Simon M. Brandl,
Laura Lozza,
Gregor Conradt,
Stefan H.E. Kaufmann,
Walter Reith,
Ivo Kwee,
Susana Minguet,
Sonia T. Chelbi,
Greta Guarda
Affiliations
Anh Thu Dang
Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland
Juliane Strietz
Department of Immunology, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany
Alessandro Zenobi
Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland
Hanif J. Khameneh
Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland
Simon M. Brandl
Department of Immunology, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany
Laura Lozza
Department of Immunology, Max Planck Institute for Infection Biology, Berlin 10117, Germany
Gregor Conradt
Department of Immunology, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany
Stefan H.E. Kaufmann
Department of Immunology, Max Planck Institute for Infection Biology, Berlin 10117, Germany; Hagler Institute for Advanced Study at Texas A&M University, College Station, TX 77843, USA
Walter Reith
Department of Pathology and Immunology, University of Geneva Medical School, 1211 Geneva, Switzerland
Ivo Kwee
Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland
Susana Minguet
Department of Immunology, Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany; Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
Sonia T. Chelbi
Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland; Corresponding author
Greta Guarda
Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland; Corresponding author
Summary: BTN3A molecules—BTN3A1 in particular—emerged as important mediators of Vγ9Vδ2 T cell activation by phosphoantigens. These metabolites can originate from infections, e.g. with Mycobacterium tuberculosis, or by alterations in cellular metabolism. Despite the growing interest in the BTN3A genes and their high expression in immune cells and various cancers, little is known about their transcriptional regulation. Here we show that these genes are induced by NLRC5, a regulator of MHC class I gene transcription, through an atypical regulatory motif found in their promoters. Accordingly, a robust correlation between NLRC5 and BTN3A gene expression was found in healthy, in M. tuberculosis-infected donors' blood cells, and in primary tumors. Moreover, forcing NLRC5 expression promoted Vγ9Vδ2 T-cell-mediated killing of tumor cells in a BTN3A-dependent manner. Altogether, these findings indicate that NLRC5 regulates the expression of BTN3A genes and hence open opportunities to modulate antimicrobial and anticancer immunity.
